http://www.gimjournal.org/article/S1098360023009097/pdf

Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations.

Craniosynostosis is a premature fusion of cranial sutures, resulting in abnormally shaped skull and brain development disorder. The description of craniosynostosis in patients with BCL11B mutations is rare. Here, we firstly report a 25-month-old Chinese boy with a novel frameshift variant in BCL11B gene. The patient was identified c.2346_2361del by whole-exome sequencing and was confirmed to be de novo by parental Sanger sequencing. This patient presented clinical phenotype of craniosynostosis as well as global developmental delay. He had a small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia and craniosynostosis. Brain MRI showed brain extracerebral interval and myelination changes, and brain CT with 3D reconstruction showed multi-craniosynostosis. Our study expands the clinical phenotypes of patients with BCL11B gene mutation, and our findings may help guide clinical treatment and family genetic counseling.

/pdf/case-report-a-novel-truncating-variant-of-bcl11b-associated-1x0h9u2r.pdf

Case report: A novel truncating variant of BCL11B associated with rare feature of craniosynostosis and global developmental delay

Advances in prenatal/neonatal genetic screening practices and next generation sequencing (NGS) technologies have made the detection of molecular causes of pediatric diseases increasingly more affordable, accessible, and rapid in return of results. In the past, families searching for answers often required diagnostic journeys leading to delays in targeted care and missed diagnoses. Non-invasive prenatal NGS is now used routinely in pregnancy, significantly altering the obstetric approach to early screening and evaluation of fetal anomalies. Similarly, exome sequencing (ES) and genome sequencing (GS) were once only available for research but are now used in patient care, impacting neonatal care and the field of neonatology as a whole. In this review we will summarize the growing body of literature on the role of ES/GS in prenatal/neonatal care, specifically in neonatal intensive care units (NICU), and the molecular diagnostic yield. Furthermore, we will discuss the impact of advances in genetic testing in prenatal/neonatal care and discuss challenges faced by clinicians and families. Clinical application of NGS has come with many challenges in counseling families on interpretation of diagnostic results and incidental findings, as well as re-interpretation of prior genetic test results. How genetic results may influence medical decision-making is highly nuanced and needs further study. The ethics of parental consent and disclosure of genetic conditions with limited therapeutic options continue to be debated in the medical genetics community. While these questions remain unanswered, the benefits of a standardized approach to genetic testing in the NICU will be highlighted by two case vignettes.

/pdf/challenges-in-the-clinical-understanding-of-genetic-testing-1peb179e.pdf

Challenges in the clinical understanding of genetic testing in birth defects and pediatric diseases

Neonatal metabolic acidosis (NMA) is a common problem, particularly in critically ill patients in neonatal intensive care units (NICUs). Complex etiologies and atypical clinical signs make diagnosis difficult; thus, it is crucial to investigate the underlying causes of NMA rapidly and provide disorder-specific therapies. Our study aims to provide an overview of the genetic causes of NMA in patients from NICUs. We performed next-generation sequencing (NGS) on neonates with NMA from January 2016 to December 2019. Clinical features, genetic diagnoses, and their effects on clinical interventions were collected for analysis. In the 354 enrolled patients, 131 (37%) received genetic diagnoses; 95 (72.5%) of them were autosomal recessively inherited diseases. Two hundred and fifteen variants spanning 57 genes were classified as pathogenic (P) or likely pathogenic (LP) in 131 patients. The leading cause was metabolic disorders due to 35 genes found in 89 patients (68%). The other 42 NMA patients (32%) with 22 genes had malformations and renal, neuromuscular, and immune-hematological disorders. Seven genes (MMUT, MMACHC, CHD7, NPHS1, OTC, IVD, and PHOX2B) were noted in more than four patients, accounting for 48.9% (64/131) of the identified P/LP variants. Forty-six diagnosed patients with uncorrected NMA died or gave up. In conclusion, 37% of neonates with metabolic acidosis had genetic disorders. Next-generation sequencing should be considered when investigating the etiology of NMA in NICUs. Based on early molecular diagnoses, valuable treatment options can be provided for some genetic diseases to achieve better outcomes.

/pdf/neonatal-metabolic-acidosis-in-the-neonatal-intensive-care-4caj2hg5ib.pdf

Neonatal Metabolic Acidosis in the Neonatal Intensive Care Unit: What Are the Genetic Causes?

Key Points Question What is the relative prevalence of congenital heart defects among boys born with hypospadias compared with boys born without hypospadias? Findings In this large multistate birth defects registry cohort study of data from population-based birth defect surveillance programs on all male infants born in 11 US states, boys born with hypospadias were 6 times more likely than boys without hypospadias to have any major congenital heart defect. Meaning This study suggests that screenings for additional birth defects among boys born with hypospadias may be warranted; in addition, molecular studies are needed to uncover the shared etiology of co-occurring defects in different developmental fields.

Prevalence and Clustering of Congenital Heart Defects Among Boys With Hypospadias

Multiple congenital anomalies (MCAs) at birth have emerged as an important cause of neonatal morbidity and mortality. This study aimed to investigate the genetic causes and characteristics of clinical outcomes in a large cohort of neonates with MCAs. Clinical exome sequencing/exome sequencing/genome sequencing were undertaken from December 1, 2016 to December 1, 2019 to detect single nucleotide variations (SNVs) and copy number variations (CNVs) simultaneously in individuals who met the inclusion criteria. A total of 588 neonates with MCAs were enrolled. One hundred sixty-one patients received diagnosis, with 71 CNVs and 90 SNVs detected, the overall diagnostic rate being 27.38%. Cardiovascular malformation was the most common anomaly (60%) and accounted for the top symptomatic proportion in both CNVs and SNVs. As the number of involved system increased from 2 to 3-4, and then to ≥5, the overall diagnostic rate increased gradually from 23.1% to 30.5%, and then to 52.2%, respectively. Patients who received genetic diagnoses were offered better clinical management or were referred to the specific disease clinic. In conclusion, this large cohort study demonstrates that both CNVs and SNVs contribute to the genetic causes of MCAs, and earlier genetic assertion may lead to better clinical management for patients.

Diagnostic and clinical utility of next‐generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project

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Diagnostic and clinical utility of next‐generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project